Proteases are enzymes which cleave proteins at specific peptide bonds and, in living systems, mediate or control a broad spectrum of biological functions, such as cleaving precursors to form active proteins in post-translational processing of polypeptides. Inhibiting proteases vital to certain biological functions thus provides a means for the treatment or prevention of disease states which rely on the action of the proteases involved.
For example, retroviral proteases, such as HIV protease, cleave large precursor polypeptides, produced in infected cells, into smaller protein components, or subunits, which are subsequently assembled to form functional virus structures. Since such proteases encoded by the viral genome play a critical role in the replication of a virus, inhibition of these enzymes provides a means for the prevention and treatment of retroviral infection. Various retroviral proteases have been disclosed for this purpose; see, for example, European Patent Application 346,847, and especially European Patent Application 580,402.
As another example, renin is a protease which cleaves angiotensinogen to form angiotensin I, the latter which is then cleaved by a second enzyme (ACE) to form angiotensin II, a potent hypertensive agent. Inhibition of renin provides a means for controlling hypertension, and inhibitors may be prepared for this purpose. See, for example, Luly et al., J. Org. Chem., 52, 1487-1492 (1987) and Evans et al., J. Org. Chem., 50, 4615-4625 (1985).
Depending on their structure, protease inhibitors, such as those described above, may be prepared using epoxide intermediates. As such epoxides may be prepared from halohydrins, methods for the preparation of the halohydrin starting materials are sought. Additionally, as with many pharmaceutical agents, the stereoconfiguration of protease inhibitors can play a role in their effectiveness. Since a protease inhibitor having a desired stereoconfiguration is often most efficiently prepared by employing the appropriate chiral precursors, stereoselective methods for the preparation of the epoxide intermediates and the halohydrin starting materials are particularly sought.